Andrew Leuchter - US grants

This application proposes Andrew Leuchter, M.D., as a candidate for the Geriatric Mental Health Academic Award, to conduct his research and teaching activities at UCLA. There are five aims in this application: 1) to foster Dr. Leuchter's development as an investigator in geriatric psychiatry; 2) to facilitate the development at UCLA of research aimed at improved methods for diagnosis and assessment of demented patients; 3) to broaden involvement by faculty in psychiatry and other departments at UCLA in geriatric mental health research; 4) to enable Dr. Leuchter to train other researchers to utilize his skills and methods; and, 5) to disseminate his research findings to other academicians at UCLA. These aims will be achieved through a five-part plan. First, Dr. Leuchter will conduct two studies during the term of his award: a) a study aimed at the development of computer-analyzed electroencephalography (CEEG) as a test for the differential diagnosis of dementia, and b) a study of psychological, social, and biological factors that may contribute to depression in patients with dementia of the Alzheimer type (DAT). Second, he will pursue a program of structured academic courses and tutorials aimed at the development of his research skills. This program will include the study of biostatistics, clinical epidemiology, and electrophysiology. Third, as a member of the faculty, he will supervise residents on the geropsychiatry service, serve as an attending in two clinics where elderly psychiatric patients are seen, and train research fellows under the auspices of two NIMH training grants. Fourth, he will enhance his clinical skills by performing clinical and research evaluations on patients in the UCLA Geropsychiatry Clinic and the West Los Angeles VA (WLA-VA) Dementia Clinic. Fifth, he will participate as an instructor in seminars, case conferences, grand rounds, and other didactic programs of the UCLA and WLA-VA Hospitals as a means of disseminating his research findings throughout the academic setting. He also will be available as a consultant to other researchers in the institution.

The accuracy of the clinical diagnosis of dementia is severely limited. This project proposes to develop computer-analyzed electroencephalography (CEEG) as a clinical test that will aid in the accurate diagnosis of dementia. It consists of a five-stop research plan. First, ninety geriatric subjects will be examined, divided equally among three groups: those with Alzheimer-type dementia (DAT), multi-infarct dementia (MID), and non-demented normals. All subjects will undergo rigorous clinical evaluations, including mental status and neuropsychological testing, neurological examination, and a battery of relevant laboratory tests. Second, electroencephalograms (EEGs) will be performed on each of the study subjects in the normal resting state and after administration of low-dose secobarbital. Digital EEG data will be collected with an IBM Personal Computer (IBM-PC) attached to the electroencephalograph during the procedures. Third, spectra and coherence functions will be calculated for multiple EEG channels from each subject using the IBM-PC. Fourth, the subjects will be followed to autopsy, wehre neuropathologic diagnoses will be established. Finally, multi-group, stepwise discriminant analysis will be performed under a "training/testing" paradigm. Using the spectra and coherence variables from half of the subjects in each category, sets of parameters will be selected which correlate most strongly with both clinical and autopsy diagnoses (training portion). The discriminant functions developed from this first analysis will then be used to categorize prospectively the other half of the subjects into both their clinical and autopsy diagnostic categories (testing portion). The results of this discriminant analysis will be analyzed to determine the sensitivity and specificity of CEEG as a diagnostic tool for dementia.

There are two aims of this renewal proposal: first, to develop computer-analyzed electroencephalography (CEEG) more fully as a tool for the differential diagnosis of dementia; and second, to begin to establish links between brain functional abnormalities seen on CEEG and structural lesions seen on magnetic resonance imaging (MRI) scans. There are six steps in this research plan. First, new subjects will be recruited for the existing cohort of subjects with Alzheimer's disease (DAT), multi-infarct dementia (MID), and normal control subjects (CON). Second, subjects will recruited for three additional groups: those with major depressive episode, dementia of affective disorder (DAD), and dementia of other etiologies. All subjects being evaluated for dementia will undergo a thorough evaluation which will include mental statu testing, neuropsychological testing, neurologic examination, a battery of relevant laboratory tests, as well as MRI scanning. Third, all subjects will undergo conventional EEG studies, which will be interpreted by an electroencephalographer, as well as CEEG studies. Fourth, all MRI scans will be quantitatively rated by two neuroradiologists for the severity and location of deep white-matter lesions, periventricular lucencies, and atrophy. MRI scans will be correlated with CEEG topographic maps to detect co-localization of functional and structural lesions. Fifth, subjects will be reassessed on an annual basis (or more frequently if suggested by their clinical situation) with an interview of subjects and family, mental status examination, EEG and CEEG procedures, and any other tests which are clinically indicated. Sixth, we will follow subjects to autopsy to confirm clinical diagnoses and to correlate MRI lesions with neuropathological findings. Specific experimental hypotheses regarding the sensitivity and specificity of CEEG measures, the significance of lesions seen on MRI, and the capacity to co- localize functional and structural lesions will be tested.

The goal of this application is to enable Dr. Leuchter's to undertake a new research program focused on cognitive neurophysiology in the elderly. Dr. Leuchter proposes to develop new skills in : 1) the use of cognitive tasks for cerebral activation; 2) the recording of neurophysiologic data during task performance; and 3) the study of cognitive changes in aging. He has selected a panel of expert consultants who will work with him to develop these skills. With the support of this Award, Dr. Leuchter will utilize his quantitative electroencephalography (QEEG) and magnetic resonance imaging (MRI) methods to examine differences in cognition between young and old adults, and to study the cognitive decline that accompanies aging. He will test the following three general hypotheses: 1. Differences in cognition between young and elderly subjects will be reflected in differences in cerebral activation and inhibition accompanying cognitive tasks: 2. Elderly subjects with deep white-matter lesions are at greater risk for cognitive dysfunction than those without these lesions; and 3. Elderly subjects with poor performance on cognitive tasks, who have white-matter lesions that affect the brain systems showing poor performance, will be at greater risk for progressive or global impairment than those without such lesions. Dr. Leuchter has developed enhanced QEEG methods that may provide more information about cerebral activation during tasks than previously possible. He will use these methods in this revised research plan to study 50 young and 100 elderly adults with QEEG during the performance of a battery of cognitive tasks. Some of the elderly subjects will have risk factors for the development of white- matter lesions. Quantitative MRI will be used both the locate recording electrodes in relation to the brain, and to determine the volume of white-matter disease. All subjects will be examined with a neuropsychological test battery, task-activated QEEG, and MRI at entry into the study and at three years. Comparisons will be performed between young and old subjects, and with groups of elderly subjects, to determine if deficient task activation is associated with poorer performance and/or cognitive decline.

The Clinical Core has accomplished the goals we established for the UCLA Alzheimer's Disease Center (ADC). We have enrolled 1261 subjects; since the competitive renewal of the Center, we have achieved an annualized follow-up rate of more than 90%. We provide research patients for over 70 studies and projects. The clinical sites of the Core serve as training venues for six Federally-funded training grants. The goals of the Clinical Core during this application period is to provide well- characterized patients with Alzheimer's disease (AD) or related disorders for participation in research projects of investigators affiliated with the UCLA Alzheimer's Disease Center (ADC). The Core will accomplish this goal through four specific aims: 1) Perform research evaluations to promote research into AD and other dementias by performing in-depth, research caliber evaluations on patients and primary caregivers, as well as comparable control subjects, at the UCLA Medical Center, Oliver View Medical Center, and Martin Luther King Medical Center/Drew University Medical School [King/Drew] Program; (2) Retain and follow subjects: to maintain high rates of longitudinal follow-up of subjects through prompting and registering annual follow-up visits, and obtaining routine antemortem consent for autopsy studies; 3) Support research projects: to support AD research projects through computer-based identification of research subjects that meet criteria for specific projects, coordinating sharing of subjects by multiple research projects and facilitating sharing of subjects across research sites; and, 4) Enhance research on ethnic minority subjects: to expand existing efforts to recruit dementia patients and control subjects from a broad range of ethnic backgrounds. The Clinical Core will achieve these aims by continued support of investigators at three clinical sites. These teams perform comprehensive, standardized diagnostic evaluations of patients. These evaluations also will include comprehensive neuropsychological testing and assessment of the behavioral and neuropsychiatric aspects of AD, as well as caregiver evaluations. The Clinical Core enhances the efforts of the Imaging and Genetics Core by gathering in-depth clinical data assessing the major domains of cognitive function, and providing this and other clinical information relevant to the interpretation of imaging and genetic studies. The Clinical Core will collaborate with the Education and Information Transfer Core to instruct clinical staff in the use of rating instruments. The Clinical ore will continue its emphasis on recruitment of subjects from ethnic minority groups, primarily at the Olive View Medical Center and King/Drew sites.

In this competing renewal application for a K02 award, Dr. Andrew Leuchter proposes a line of research and career enhancement aimed at improving outcomes of treatment for depression. Between 25 - 40 percent of patients with depression fail to respond to the first antidepressant prescribed, and these patients may suffer a protracted course of depression. Preliminary studies indicate that brain function measured with quantitative electroencephalographic (QEEG) cordance may be used prior to treatment, to predict which antidepressant medication is most likely to benefit an individual patient, as well as after treatment has started, to detect antidepressant effectiveness before symptoms improve. This application has three specific aims: 1) to verify the discriminative power of cordance in predicting and detecting treatment response for two antidepressants with different mechanisms of action; 2) to establish the relationship of cordance measurements to other putative predictors of antidepressant response, including cerebral metabolism and structure as well as clinical factors (age and symptom type); and, 3) in a developmental aim, to enhance Dr. Leuchter's skill in the areas of measuring treatment outcome and assessing the impact of predictors on treatment effectiveness. For his primary research study, Dr. Leuchter proposes a plan which will enroll 96 younger and older adult subjects in a double-masked protocol. Subjects will be treated with either fluoxetine 20/40 mg. or venlafaxine 150/225 mg., to determine whether cordance measurements are reliably associated with differential short-term response to antidepressant medications. Putative predictors of response such as pre- and post-treatment FDG-PET, volumetric MRI measurements, and clinical symptoms will be examined to identify the physiologic processes and structural features which contribute to the association between cordance and short-term treatment outcome. This study is part of an overall plan to enhance Dr. Leuchter's research activities and skills in interventions outcomes research. He will work with two consultants, Drs. Kenneth Wells and Lynn Fairbanks, to implement new methods and enhance his skills in intervention outcomes research. He will expand his research to include new methods to examine patterns of response, and will utilize additional functional outcome measures. In a developmental phase of this study, he also will initiate projects to examine the effectiveness of cordance and other putative predictors in improving long-term treatment outcomes. These effectiveness projects will include introduction of predictors into the usual treatment setting, and examination of cost-effectiveness and long-term treatment outcomes.

DESCRIPTION (provided by applicant): Major depressive disorder (MDD) has among the highest placebo response rates of any medical illness. Many MDD subjects in clinical trials who undergo treatment with placebo show improvement comparable to those receiving antidepressant medication. Previous research indicates that interpersonal factors and patient characteristics underlie both medication and placebo response in depression, making MDD an excellent illness model for understanding the origins of the placebo response. This application proposes a line of clinical investigation that will elucidate the role of interpersonal factors and patient characteristics in contributing to improvement seen in placebo treatment of MDD. This study will achieve the following four specific aims: 1) to determine whether administration of placebo or medication pills has effects on improvement of symptoms in addition to interpersonal clinical interaction (ICI) for subjects with MDD; 2) to determine whether pretreatment expectations and the strength of the pharmacotherapeutic alliance are related to the likelihood of clinical improvement during interpersonal clinical interaction, placebo, and medication treatment conditions; 3) to determine if there are pretreatment neurophysiologic, symptom, or cognitive characteristics of subjects that are associated with response to placebo in MDD; and, 4) to examine the effects of interpersonal clinical interaction, placebo pill administration, and medication administration, on brain function in subjects with MDD. We will achieve these aims through a three-step research plan. First, we will enroll 120 subjects meeting criteria for moderate to moderately severe recurrent MDD into one of three treatment conditions: 1) interpersonal clinical interaction (ICI) (thorough baseline assessment and subjects interacting with clinical research personnel on a fixed schedule); 2) placebo treatment (PBO) (assessment and interaction as in ICI plus double-blinded treatment with placebo tablets); and 3) medication treatment (MED) (assessment and interaction as in ICI plus double blinded treatment with antidepressant medication). Second, all subjects will be assessed prior to treatment assignment with measures of pharmacotherapeutic alliance with study personnel, expectation regarding treatment, cognitive processing speed, emotional and neurovegetative symptoms of depression, as well as brain electrical activity. Third, subjects will be assessed over the course of eight weeks of treatment with ratings of symptom change, as well as changes in pharmacotherapeutic alliance, expectation, and brain function. At the end of eight weeks, blind will be broken and all subjects referred for naturalistic treatment where they will be eligible to receive medication free-of charge for 10 months. In addition to testing the specific hypotheses, we plan an exploratory analysis in which we will examine factors that may influence placebo response, such as personality characteristics, perceived social support, and health locus of control. The results of this project will lead to better understanding of the mechanisms of the placebo response in MDD.

DESCRIPTION (provided by applicant): The long-term objective of the T32 UCLA Interdepartmental Clinical Pharmacology Postdoctoral Training Program (ICPTP) is to produce clinical pharmacologists who have expertise in conceptualizing and implementing hypothesis driven, data based clinical pharmacology research; are competent clinically to achieve therapeutics of the highest quality; and are motivated to educate future clinical pharmacologists. The benchmarks of this successful program will be progress in clinical pharmacology research, improved therapeutic outcomes and decreased complication rates, all contributing to increased efficiency of the health care system. The diversity of the UCLA ICPTP has been confirmed both through the association of the David Geffen School of Medicine at UCLA with the Charles Drew University of Medicine and Science and by the specialties of the trainees, who have been MD or MD/PhD junior faculty with primary appointments in Anesthesiology/Critical Care Medicine, internal Medicine (Gastroenterology, Pulmonary, (Allergy/Immunology), Neurology, Obstetrics and Gynecology, Otolaryngology (Head and Neck Surgery), Pediatrics (Gastroenterology, Liver Transplantation, Immunotherapy, Pediatric Endocrinology), Psychiatry and Surgery (Liver Transplantation). This association and breadth of trainee areas of expertise broaden and enrich the T32 UCLA ICPTP curricular experience.

Project Summary/Abstract Alzheimer?s Disease (AD) affects millions of people in the US and worldwide, and is becoming an increased burden on individual and society. Individuals with amnestic mild cognitive impairment (aMCI) are at greater risk for development of AD. A reliable method of treatment for individuals with aMCI could help not only to improve the lives of elderly individuals with memory impairment, but also potentially prevent or delay the development of AD. Theta burst transcranial magnetic stimulation (TBS) is a non-invasive neuromodulation method that shows promise for improving memory and may be applied to brain areas that are functionally connected to the hippocampus in order to restore memory function. Because the ability to apply stimulation to modify memory functions depends on the application of stimulation at distinct and specific sites in the complex neuronal circuitry underlying these functions, neuroimaging guided targeting of TBS treatment will provide individualized tailoring of therapeutic intervention needed for maximum efficacy. The proposed project will therefore implement a novel high-resolution functional magnetic resonance imaging (fMRI) guided TBS method to improve hippocampal-cortical connectivity and consequent episodic memory in elderly aMCI individuals with and without genetic risk for AD. Functional MRI, scalp electroencephalography (EEG), and genetic testing will also be used to characterize brain network changes and genetic factors that are associated with TBS related memory restoration. The implications of TBS related memory restoration to patients affected with disorders of memory is of great significance and of urgent need. The proposed project will therefore develop a novel method for memory enhancement, characterize associated brain changes, contribute to the understanding of hippocampal-cortical networks and their role in memory, and ultimately provide a novel therapeutic approach to human memory disorders. The data from this project will demonstrate a proof-of-concept that TBS can be used to improve memory in aMCI, and will launch an emerging and pivotal area of research that will provide therapeutic interventions for patients afflicted with life debilitating cognitive disorders.